The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents

The new generation hypnotic drugs, zolpidem, zopiclone and zaleplon, are at least as efficacious in the clinic as benzodiazepines and may offer advantages in terms of safety. These drugs act through the BZ binding sites associated with GABA(A) receptors, but show some differences from benzodiazepines in pharmacological effects and mechanisms of action. Of particular interest is the finding that zolpidem shows a wide separation between doses producing sedative effects and those giving rise to other behavioural actions, and induces less tolerance and dependence than benzodiazepines. Zolpidem also demonstrates selectivity for GABA(A) receptors containing alpha(1) subunits. Recent studies using genetically modified mice have confirmed that receptors containing alpha, subunits play a particularly important role in mediating sedative activity, thus providing an explanation for the pharmacological profile of zolpidem.